Atherosclerosis is a condition in which abnormal amounts of lipids are deposited in certain arteries, resulting in intimal thickening. The condition manifests itself by circulatory occlusion, principally of the coronary, cerebral, and peripheral arteries. Ensuing complications can lead to coronary heart disease, cerebrovascular disease, and some forms of peripheral vascular disease. These conditions are the major causes of death in the United States.
It has long been known that there is a relationship between atherosclerosis and high levels of plasma particularly cholesterol. In fact, hypercholesterolemia is a primary risk factor for coronary heart disease. In humans more than one-half of total body cholesterol is derived from de novo synthesis. Drugs that can be used to reduce the quantity of cholesterol thus biosynthesized are of potential value in treating hypercholesterolemia, and may also have utility as prophylactic agents for general use against atherosclerosis and coronary heart disease.
It has been discovered fairly recently that compactin (Formula 1) and a related compound, mevinolin (Formula 2) display utility as inhibitors of the enzyme hydroxymethylglutaryl coenzyme A reductase ("HMG CoA reductase"). ##STR1## See, e.g., U.S. Pat. No. 4,049,495, U.S. Pat. No. 4,137,332, and U.S. Pat. No. 3,983,140, all issued to Endo et al. This class of natural products, distinguished by a highly functionalized hexalin or octalin unit and a .beta.-hydroxy-.delta.-lactone portion linked by an ethylene bridge, are collectively referred to as mevinic acids. It has been demonstrated that the active form of these mevinic acids is the corresponding open-chain dihydroxy acid given by Formula 3 (as above, for compactin, "R" corresponds to -H; for mevinolin, to -CH.sub.3). ##STR2##
Formula 3 HMG CoA reductase catalyzes formation of mevalonate, a precursor in cholesterol biosynthesis, from HMG CoA, and is in fact the rate-controlling enzyme in the process. Thus, because compactin and mevinolin are potent as inhibitors of the biosynthesis of cholesterol, synthesis of these and related compounds is of some interest.
The first total synthesis of (+)-compactin was presented in 1981 by Wang et al. (Wang, N.-Y., Hsu, C.-T., and Sih, C.J., "Total Synthesis of (+)-Compactin," J. Am. Chem. Soc. 103, 6538 (1981); see also Hsu, C.-T., Wang, N.-Y., Latimer, L.H., and Sih, C.J., "Total Synthesis of the Hypercholesterolemic Agent Compactin," J. Am. Chem. Soc. 105, 593 (1983)), the key steps of which involve preparation of the enone shown in Formula 4, the cuprate of Formula 5, and admixture thereof. ##STR3## Although in this way (+)-compactin is ultimately synthesized in approximately a 0.8% yield, the reaction sequence is a lengthy, complicated process involving harsh reaction conditions (thus necessitating protecting groups) and separation of stereoisomers at several intermediate points. A similar, "linear" synthesis of compactin has been presented by a different group and employs similar synthetic techniques (Girotra, N. et al., "A New Route in the Sequential Total Synthesis of Compactin," Tetrahedron Lett. 24, 3687 (1983)); however, similar problems have also been encountered.
Still another synthesis of (+)-compactin has been reported involving an intramolecular Diels-Alder reaction as the central synthetic maneuver (Hirama, M. et al., "Chiral Total Synthesis of Compactin," J. Am. Chem. Soc. 104, 4251 (1982)). A compound given by the structure shown in Formula 6 is synthesized by a WadsworthEmmons coupling, caused to cyclize, and then esterified. ##STR4## A similar method has been used to achieve synthesis of (+)-mevinolin. These syntheses share some of the difficulties encountered in the Wang et al. process outlined above, i.e. with regard to number of steps, use of harsh reagents, production of racemic mixtures rather than the enantiomerically pure compounds, etc. An additional problem encountered with the Hirama et al. syntheses is production of the desired stereoisomer as a minor product.
Several other syntheses appear in the patent literature. U.S. Pat. No. 4,440,927 to Prugh shows a method of synthesizing antihypercholesterolemic compounds such as compactin and mevinolin using a biphenyl-based compound (which becomes a substitute for the lower, "hexalin" portion of the molecule) and a chiral synthon (which becomes the lactone moiety). U.S. Pat. No. 4,474,971 to Wareing shows a method of making pyranone compounds, which, like compactin and mevinolin, are inhibitors of HMG CoA reductase. This latter method utilizes chemistry similar to that disclosed by Prugh for the upper portion of the molecule, although different protecting groups are employed; the process also involves use of a Wittig reagent. Problems with steric hindrance and other problems can easily arise with the Wittig reagents used.
The prior art methods of synthesizing compactin, mevinolin, and related compounds are for the most part lengthy, complicated syntheses which employ fairly harsh reagents and thus necessitate the use of protecting groups. A number of these prior methods also require separation of stereoisomers at intermediate points throughout the syntheses, further reducing the overall yield of the desired compounds and increasing the time as well as the number of synthetic steps involved. As may be seen, then, there is a need in the art for a total synthesis of compactin, mevinolin and related compounds which uses relatively few steps, mild reagents, and mild reaction conditions generally, which obviates the need for protecting groups, and ultimately provides the desired compounds in a high yield as well as in enantiomerically homogeneous form.